A Brief Guide to Understanding: FDA’s CMC Guidance for Phase 2 and 3 INDs

Introduction

Understanding the Chemistry, Manufacturing and Controls (CMC) Guidance for Phase 2 and 3 Investigational New Drug Applications (INDs) is a critical yet often daunting task for drug developers. The purpose of this short guide is to help drug developers navigate the CMC guidance and develop an effective strategy for meeting the regulatory requirements.

Overview

The Chemistry, Manufacturing, and Controls (CMC) Guidance issued by the U.S. Food & Drug Administration (FDA) outlines the requirements for filing an Investigational New Drug Application (IND) during clinical trials in Phases 2 and 3. The guidance details what information needs to be included in an IND submission, such as detailed specifications of starting materials; process controls that can be used to assure quality, purity, and consistency of the product throughout production; packaging and labeling considerations; stability data; and batch records that establish reproducibility of manufacturing processes.

The IND

The Quality section (CTD Module 3) of an Investigational New Drug (IND) application submitted to the FDA is a crucial aspect of the drug development process. The CMC section provides information on the drug substance, drug product, and manufacturing processes.

• Purpose: The purpose of the CMC section is to provide the FDA with information on the quality, purity, and consistency of the drug substance and drug product, as well as the processes used to manufacture them.
• Content: The CMC section should include information on the drug substance, including its composition, characterization, and specifications. Information on the drug product should include its formulation, manufacturing process, and controls. The section should also include a description of the manufacturing facility and a description of the quality control unit and its responsibilities.
• Phase 2: In Phase 2, the focus is on establishing the safety and efficacy of the drug in a small number of patients. The CMC section should include a summary of the results of preclinical studies and information on the drug substance and drug product that supports their quality and consistency.
• Phase 3: In Phase 3, the drug is tested in a larger number of patients to further establish its safety and efficacy. The CMC section should include a more detailed description of the drug substance and drug product, as well as the manufacturing processes and controls. The section should also include a description of the stability program for the drug product and a plan for ongoing monitoring of its quality.
• Review Process: The FDA will review the CMC section to assess the quality, purity, and consistency of the drug substance and drug product, as well as the manufacturing processes used to produce them. The FDA will also assess the adequacy of the manufacturing facility and the quality control unit.
• Changes: Any changes to the drug substance, drug product, or manufacturing processes must be reported to the FDA in a timely manner. The FDA will review these changes to ensure that they do not have an adverse impact on the quality, purity, or consistency of the drug.
  

The Requirements

To make sure that a product is suitable for use in humans during clinical studies, there are specific requirements set out by FDA in regard to chemistry, manufacturing, safety testing, and stability evaluation for drug substances in Phase 2/3 INDs:

• Drug substances should meet all applicable non-clinical safety requirements prior to commencing human clinical trials.
• Drug substance must be adequately characterized with respect to identity including chemical structure; physical form; purity or related substances content; impurities profile including those present at trace levels; physicochemical properties relevant to manufacturability of the product; the analytical methodology used for determining quality attributes etc.
• Manufacturing processes must include adequate control measures to ensure consistent production of drug substances throughout their life cycle in terms of identity, strength, quality, and purity characteristics.
• Packaging components must be validated as compatible with other ingredients used in formulation before being filled into containers/packaging systems used at commercial scale quantities.
• Stability assessment should be conducted on manufactured products before they go into clinical use. Samples should be stored under specified conditions determined through accelerated stress testing so that any potential degradants can be identified in advance. * Any changes made after batch release must be documented along with additional supportive data if needed.*

https://www.fda.gov/media/70822/download

Moving from Phase 2 to Phase 3

Moving from Phase 2 to Phase 3 of the clinical trial development process involves meeting specific Quality requirements as outlined in the Chemistry, Manufacturing, and Controls (CMC) Guidance issued by the U.S. Food & Drug Administration (FDA). This guide provides information about the quality requirements for Investigational New Drug Applications (INDs) in Phases 2 and 3.

The CMC guidance defines requirements that must be met when submitting an IND to the FDA during Phases 2 and 3 of drug development, including detailed specifications of starting materials; process controls that can ensure consistency and quality of product throughout production; packaging and labeling considerations; stability data; and batch records that establish reproducibility of manufacturing processes. All information must be presented in a way that allows for a comprehensive assessment of safety, effectiveness, and manufacturing consistency across batches.

Quality Requirements for Moving from Phase 2 into Phase 3

To move from Phase 2 into Phase 3, there are specific Quality Requirements set out by FDA that must be met:

• An acceptable description of how all required starting materials will be obtained should be included in the IND submission with evidence that they comply with all applicable regulatory standards.
• An appropriate system of process control measures should be clearly defined, validated, implemented, and monitored to ensure uniformity between successive batches with respect to identity, strength, quality, purity characteristics, or other attributes relevant to therapeutic indices/activity.
• A risk assessment should be conducted prior to scale-up based on changes made during development or scale-up activities focusing on identifying potential risks affecting the quality or efficacy of the drug substance/product and defining appropriate control measures if necessary. An impact assessment is also recommended which looks at any unintended consequences due to changes made during the manufacture or design of product-related activities such as formulation and packaging processes.
• Appropriate analytical characterization studies should also be conducted on the final drug substance/product before it is released depending upon its intended use in clinical trials so any unexpected degradation products can be identified earlier by performing accelerated stress testing conditions like temperature/humidity etc.
• Storage instructions for finished products should incorporate accelerated stability studies to achieve satisfactory shelf-life for prolonged storage periods as specified by FDA regulations. * Any significant changes after batch release must include additional supportive data if needed.*

Conclusion

Developing drugs from Phase 2/3 INDs requires comprehensive knowledge of various aspects such as non-clinical safety requirements, characterization studies, process development, and validation activities as well as stability assessments prior to commencing human clinical trials due diligence on part of both sponsor companies and investigators involved in trial management. The guidance published by FDA serves as a helpful insight into their regulatory pathways so sponsors can ensure their product meets all criteria before it’s ready for market release.

The CMC guidance outlines specific Quality Requirements when moving from Phase 2 into Phase 3 so sponsors can ensure their product meets these criteria before going through pivotal human trials. The guidance serves as a helpful insight into their regulatory pathways so sponsors can develop an effective strategy for meeting the regulatory requirements effectively while staying compliant with FDA regulations.